Genetic epidemiology of breast cancer: risk, instability & statistical methods Breast cancer is a major source of morbidity and mortality, and remains the most common cancer occurring in U.S. women. In this application, we will study two aspects of breast cancer development: germline mutations as in two major tumor suppressor genes BRCA1 and BRCA2 and somatic mutations characterized by changes in copy number and allelic loss. The first aim is on the development and evaluation of statistical methods for population-based case-control family studies of candidate genes like BRCA1 and BRCA2. This includes (a) estimating age-dependent penetrance function from a two-stage case-control study of BRCA1/2 mutations and further developing the methods to include extended families and classification of polymorphisms of unknown significance; (b) extended the approach in (a) to a general multivariate survival model for flexibly modeling the different types of relatives; (c) using the estimates in (a) to estimate the carrier probabilities and disease risk for a counselee in a counseling situation. The second aim is on the method development for analyses of genomic instability data. Genomic instability data includes copy number change data from the array-comparative genomic hybridization (array-CGH) and allelic loss data from the genome-wide genotyping technology. For array-CGH data, we will develop methods for quantifying the segmentation and derive the underlying discrete copy numbers. For both array- CGH and allelic loss data, we will identify oncogenic network using the graphical modeling. The methods will be applied to two studies of genomic instability in breast cancer. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]